Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor (FGFR) family, in which there is high amino acid sequence conservation between family members. Members of the FGFR family are differentiated by both ligand binding affinities and tissue distribution. A full-length FGFR polypeptide contains an extracellular domain (ECD), a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. The ECD of FGFR polypeptides interacts with fibroblast growth factors (FGFs) to mediate downstream signaling, which ultimately influences cellular differentiation. In particular, activation of the FGFR3 protein plays a role in bone development by inhibiting chondrocyte proliferation at the growth plate and limiting bone elongation.
Gain-of-function point mutations in FGFR3 are known to cause several types of human skeletal growth retardation disorders, such as achondroplasia, thanatophoric dysplasia type I (TDI), thanatophoric dysplasia type II (TDII), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia, and craniosynostosis syndromes (e.g., Muenke syndrome, Crouzon syndrome, and Crouzonodermoskeletal syndrome). Loss-of-function point mutations in FGFR3 are also known to cause skeletal growth retardation disorders, such as camptodactyly, tall stature, and hearing loss syndrome (CATSHL). Achondroplasia is the most common form of short-limb dwarfism and is characterized by disproportionate shortness of limbs and relative macrocephaly. Approximately 97% of achondroplasia is caused by a single point mutation in the gene encoding FGFR3, in which a glycine residue is substituted with an arginine residue at position 380 of the FGFR3 amino acid sequence. Upon ligand binding, the mutation decreases the elimination of the receptor/ligand complex resulting in prolonged intracellular signaling. This prolonged FGFR3 signaling inhibits the proliferation and differentiation of the cartilage growth plate, consequently impairing endochondral bone growth.
There exists a need for improved therapeutics that target dysfunctional FGFR3 for treating skeletal growth retardation disorders, such achondroplasia.